EP1638404A1 - Parasiticidal, repellent composition for topical use on domestic animals - Google Patents
Parasiticidal, repellent composition for topical use on domestic animalsInfo
- Publication number
- EP1638404A1 EP1638404A1 EP04740530A EP04740530A EP1638404A1 EP 1638404 A1 EP1638404 A1 EP 1638404A1 EP 04740530 A EP04740530 A EP 04740530A EP 04740530 A EP04740530 A EP 04740530A EP 1638404 A1 EP1638404 A1 EP 1638404A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- permethrin
- skin
- weight
- composition
- parasiticidal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N53/00—Biocides, pest repellants or attractants, or plant growth regulators containing cyclopropane carboxylic acids or derivatives thereof
Definitions
- the invention relates to a parasiticidal and repellant composition for topical use on domesticated animals with the pyrethroid permethrin as active ingredient.
- pyrethroids have shown good activity against ectoparasites. Suitable pyrethroids include permethrin, phenothrin, cypermethrin, cyhalothrin, tralomethrin, deltamethrin, tralocythrin and flumethrin, etc.
- the most preferred pyrethroid for use in this invention is permethrin, i.e. 3- (phenoxyphenyl) methyl (1 RS) -cis, trans-3- (2,2-dichloroethenyl) -2,2-dimethylcyclopropane carboxylate.
- Ectoparasites such as ticks, fleas, lice, hair lice and mites are often found on mammals such as dogs. Ectoparasites feed on their host animal and are a constant source of irritation for the animal. In addition, they have become important as transmitters of pathogens (borreliosis, istheme, etc.). It is therefore desirable to prevent and eliminate such infestations. What is meant by this is that all parasites on the wharf are desirably killed and the infestation is reduced.
- compositions and methods for controlling and controlling ectoparasites are systemic products, that is to say those are those which contain active substances which penetrate into the animal's bloodstream to cause the insecticidal infection.
- DE 3531 920 A1 describes a process for the production of an agent for controlling ectoparasites in goats in the pouring process.
- the agent contains 0.01 to 50 parts by weight of the pyrethroids cyfluthrin, fenfluthrin, flumethrin, cypermethrin, deltamethrin, their stereoisomers, enantiomers or mixtures and a Skin-compatible diluent and, if necessary, emulsifiers and auxiliaries.
- Adhesion promoters, surfactants and spreading agents mentioned as suitable auxiliaries.
- DE 35 29 693 A1 describes an agent for a method for treating herd animals and socialized animals for combating ectoparasites.
- the agent contains cyfluthrin, flumethrin, cypermethrin, deltamethrin, fenfluthrin, their enantiomers or diastereomers or mixtures thereof in addition to skin-compatible diluents and, if appropriate, emulsifiers and other auxiliaries.
- the concentration of the active ingredient is 0.01 to 10% by weight.
- GB-A-2088212 discloses a liquid composition containing up to about 50% by weight of a pyrethroid and including a method for its topical application. Specifically, GB-A-2088212 discloses the solution of solid pyrethroids in liquid formulation using undesirable irritating organic solvents such as xylene, toluene and cyclohexanone optionally in conjunction with alkyl glycol ether.
- EP 0518 989 B1 and DE 691 26776 T2 disclose liquid compositions of more than 50% by weight and up to 85% by weight of a pyrethroid and a carrier which is an alkyl glycol ether, for a composition for controlling ectoparasites on domesticated To produce mammals selected from rats, mice, rabbits, dogs, cattle, poultry, pigs and horses by topical application.
- the invention mentioned comprises 65% to 85% by weight of permethrin and an alkyl glycol ether as carrier. It is pointed out as new and surprising that this concentrating formulation does not cause any irritation or toxicity on the skin. It would be expected that such highly concentrated solutions of a pyrethroid, when applied to and absorbed from the skin, would also be systemic would cause toxicity.
- the auxiliaries (solvents) used in patents EP 0518989 B1 and DE 691 26776 T2 belong to the class of alkyl glycol ethers. These are almost odorless liquids with a high boiling point, very good solubility in water and very good miscibility with organic solvents. Alkyl glycol ethers are mostly hygroscopic liquids that are considered non-toxic, at least when dermally applied (LD 50 dermal rabbit 6450 mg / kg body weight). Their use in dermatology as a penetration-enhancing aid is controversial, since it can also reduce penetration, depending on the formulation. In particular, the hygroscopic properties this group of solvents may also be disadvantageous with regard to the penetration of hydrophobic active substances through the skin.
- the composition after application to the skin of the animal to be treated is in contact with water, e.g. washed off the animal by rain or bathing. This causes economic damage because the solution must then be reapplied.
- the permethrin released into the environment can unnecessarily pollute the environment.
- Another disadvantage of this composition is that, due to the hygroscopic properties of the alkyl glycol ether, the solution quickly absorbs water, which causes undesirable cloudiness in the composition. In order to prevent this cloudiness, complex and expensive conditions must be observed during the preparation of the composition.
- the invention is concerned with the problem of providing a parasiticidal and repellant composition with the active ingredient permethrin for topical use on domesticated animals which is highly effective and easy to use, does not cause skin irritation in the area of application and is inexpensive and environmentally friendly to produce or use ,
- permethrin is dissolved in isopropyl myristate in a very high concentration of 50 to 90% by weight.
- this carrier in particular not only acts as a solvent, but at the same time assumes a carrier function (transport function) and quickly transports the permethrin away from the surface of the skin into the deep fat layers of the cornea (stratum cornum), those of the epidermis (Epidermis) and it no longer causes skin irritation but is still effective. At the same time, this rapid transport of permethrin away from the skin surface prevents washing out by contact with water.
- insecticidal composition of the present invention with such a high percentage of the active ingredient permethrin as active ingredient and isopropyl myristate as carrier is effective against ectoparasites and, in contrast to the aforementioned inventions and the drug approvals resulting therefrom, does not cause any skin irritation and causes skin damage.
- the composition according to the invention with a permetrin content which would lead to skin intolerance without isopropyl myristate, permits the administration of small, easily applicable doses in conjunction with the solvent mentioned without side effects. No special expertise is required for this, as is the case with administration using a syringe. The forced administration of tablets, which is often dangerous for the pet owner, is also avoided.
- Permethrin has a molecular weight of 391.29 g / mol and technical permethrin comprises approximately 25 to 80% by weight of ice and approximately 20 to 75% by weight of trans-isomer.
- Technically produced permethrin is particularly suitable for the present invention.
- a minimum amount of the trans-isomer of approximately 45% by weight and a minimum amount of the cis-isomer of 35% by weight are particularly suitable.
- the composition contains 65% by weight of permethrin and 35% by weight of isopropyl myristate as a carrier, the permitrin preferably having a minimum amount of the trans-isomer of 45% by weight and a minimum amount of the cis-isomer of 35 % By weight.
- Fatty acid esters, especially isopropyl myristate are characterized by high oxidative and hydrolytic stability. A special property of this substance is the excellent spreadability (distribution on the skin) and the particularly quick absorption into the upper layers of the skin. With excellent miscibility with oils and lipophilic substances, the substance is not miscible with water.
- the carrier substance in conjunction with hydrophobic substances allows the carrier substance to penetrate rapidly into the lipid areas of the subcutis or, more precisely, into the area of the fatty, deep-lying layers of fur of the cornea (stratum cornum), that of the epidermis ) are attributable to leads.
- the permethrin does not penetrate the blood vessels located there, which would have the consequence that the permethrin would have a systemic effect and could, for example, trigger undesired lethargy.
- the present invention is based on the finding that a faster penetration of the permethrin through the outer skin layer increases the rate of absorption of the drug and thus reduces the length of stay on the skin.
- an increase in dose is achieved indirectly by using the solvent used for a faster and stronger absorption of the active substance into the subcutaneous fatty tissue or more precisely into the area of the fat-containing, deep-lying layers of the cornea (stratum cornum).
- Isopropyl myristate is also not hygroscopic, so that there are no galenical problems in the form of turbidity during production. Accordingly, no expensive measures to prevent this clouding are necessary.
- Other solvents could be organic substances such as simple and polyhydric alcohols, esters, ketones, organic salts and acids if their physical and toxic properties correspond to the carrier isopropyl myristate used and are compatible with permethrin.
- 1-butanol and triglycerides with medium-chain fatty acids are particularly suitable, in particular a mixture of triglyceride esters of saturated, medium-chain fatty acids, mostly of natural origin, with a small proportion of unsaturated fatty acids. These substances have good stability and excellent skin penetration properties.
- Distribution agents attractants, repellents, adhesion promoters, spreading agents, stabilizers, conditioners, perfumes, fur gloss agents and color agents can be added to the present composition as further ingredients. Such substances are known from the literature and are widely used in the cosmetic industry.
- the pyrethroid is heated to 65 ° C to 80 ° C to completely dissolve any crystals present.
- the liquid solvent is placed in a separate, non-heated reaction vessel to which the permethrin is added and mixed until uniform.
- Pharmaceutical and cosmetic additives can be added to the reaction vessel beforehand.
- the composition can be administered to the host animal by any conventional local application method. It is known from the literature that a 1 ml volume of the preferred liquid composition is sufficiently effective in dogs with less than 15 kg of body weight given the concentration and amount of active ingredient described. A 1-2 ml volume of the preferred 65% by weight permethrin (65 mg to 130 mg permethrin) is sufficient for dogs larger than 15 kg. For this, 1 ml of the solution mentioned is placed between the shoulder blades and 1 further ml of the Bulwark, ie applied at the upper end after the hair was split.
- Compositions according to the invention are listed and explained below by way of example:
- the above skin tolerance study was carried out by five independent practicing veterinarians and a pharmaceutical expert. It included dogs of different breeds, female and male, from the age of 10 weeks to 8 years. A weak skin reaction was observed in two cases (product 1). All other animals showed no side effects in the days after the application, as described for example when using 2- (2-methylethoxy) ethanol according to the product information EXSPOT ® .
- the products used which have been tested in a simple blind study, can be used without any problems and, because of their unresponsive application, represent an advance over the previous formulation.
- the tested carriers are suitable for different packaging forms (glass, plastic) due to their chemical-physical behavior.
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- Life Sciences & Earth Sciences (AREA)
- Dentistry (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Agronomy & Crop Science (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a parasiticidal, repellent composition for topical use on domestic animals, said composition containing permethrin as the active ingredient. Said composition, which is highly effective and easy to apply, is kind to the skin, cost-effective and environmentally friendly as it contains between 50 and 90 wt. % permethrin or its stereoisomers and isopropyl myristate in quantities amounting to 100 wt. %.
Description
Parasitizide und repellierende Zusammensetzung zur topischen Anwendung auf domestizierten Tieren Parasiticides and repellant composition for topical use on domesticated animals
Die Erfindung betrifft eine parasitizide und repellierende Zusammensetzung zur topischen Anwendung auf domestizierten Tieren mit dem Pyrethroid Permethrin als Wirkstoff.The invention relates to a parasiticidal and repellant composition for topical use on domesticated animals with the pyrethroid permethrin as active ingredient.
Pyrethroide haben literaturbekannt eine gute Wirksamkeit gegen Ektoparasiten gezeigt. Geeignete Pyrethroide umfassen Permethrin, Phenothrin, Cypermethrin, Cy- halothrin, Tralomethrin, Deltamethrin, Tralocythrin und Flumethrin usw.. Das am meisten bevorzugten Pyrethroid zur Verwendung bei dieser Erfindung ist Permethrin, d.h. 3-(Phenoxyphenyl)methyl(1 RS)-cis,trans-3-(2,2-dichlorethenyl)-2,2- dimethylcyclopropancarboxylat.As is known from the literature, pyrethroids have shown good activity against ectoparasites. Suitable pyrethroids include permethrin, phenothrin, cypermethrin, cyhalothrin, tralomethrin, deltamethrin, tralocythrin and flumethrin, etc. The most preferred pyrethroid for use in this invention is permethrin, i.e. 3- (phenoxyphenyl) methyl (1 RS) -cis, trans-3- (2,2-dichloroethenyl) -2,2-dimethylcyclopropane carboxylate.
Ektoparasiten wie Zecken, Flöhe, Läuse, Haarlinge und Milben werden auf Säugetieren wie Hunde häufig gefunden. Ektoparasiten ernähren sich von ihrem Wirtstier und stellen eine ständige Irritationsquelle für das Tier dar. Darüber hinaus haben sie als Überträger von Krankheitserregern Bedeutung erlangt (Borreliose, Istheme usw.). Es ist daher wünschenswert, derartige Befalle zu verhindern und zu eliminieren. Damit ist gemeint, daß erstrebenswerterweise alle Parasiten auf dem Wirft getötet werden und der Befall reduziert wird.
Es gibt bekannte Zusammensetzungen und Verfahren zur Kontrolle und Bekämpfung von Ektoparasiten, von denen jedoch die meisten systemische Produkte sind, d.h. daß es sich dabei um solche handelt, die Wirkstoffe enthalten, die in die Blutbahn der Tiere eindringen, um den insektiziden Infekt hervorzurufen. Systemische Insektizide sind trotz ihrer ausgezeichneten Wirksamkeit weniger wünschenswert, wenn andere nahezu gleichwertige, äußerlich zu verwendende Möglichkeiten bestehen. Unabhängig davon haben sie außer ihrer Wirksamkeit gegen Flöhe kaum oder gar keine Wirksamkeit bei der Kontrolle des Zeckenbefalls. Sie müssen mit Hilfe von Injektionen oder Tabletteneingabe verabreicht werden, beides Applikationsformen, die häufig auf Schwierigkeiten stoßen, gefährlich sein können und von den Tierbesitzern meistens abgelehnt werden.Ectoparasites such as ticks, fleas, lice, hair lice and mites are often found on mammals such as dogs. Ectoparasites feed on their host animal and are a constant source of irritation for the animal. In addition, they have become important as transmitters of pathogens (borreliosis, istheme, etc.). It is therefore desirable to prevent and eliminate such infestations. What is meant by this is that all parasites on the wharf are desirably killed and the infestation is reduced. There are known compositions and methods for controlling and controlling ectoparasites, but most of them are systemic products, that is to say those are those which contain active substances which penetrate into the animal's bloodstream to cause the insecticidal infection. Systemic insecticides, despite their excellent efficacy, are less desirable if there are other almost equivalent external uses. Regardless of this, apart from their effectiveness against fleas, they have little or no effectiveness in controlling tick infestation. They have to be given by injection or tablet, both forms of administration that often encounter difficulties, can be dangerous and are mostly rejected by pet owners.
Die DE 101 17676 A1 beschreibt ein Zweiwirkstoffgemisch mit 35 bis 60 Gew.-% des Wirkstoffs Permethrin und 2,5 bis 12 Gew.-% des Wirkstoffs Imidacloprid oder Imidaclopridanalogon. Als Trägerstoff der Wirkstoffe wird N-Methylpyrrolidon eingesetzt. Weitere übliche, pharmazeutisch annehmbare Hilfsstoffe wie z.B. Spreitmittel und Tenside können zugesetzt sein. Zwar wird in der Druckschrift behauptet, das Mittel habe eine ausgezeichnete Hautverträglichkeit. Das von der Anmelderin dieser Patentanmeldung vertriebene Produkt mit identischer Zusammensetzung führt jedoch als mögliche Nebenwirkungen bei Hunden eine vorübergehende Überempfindlichkeit der Haut (einschließlich verstärkter Juckreiz, Haarausfall und Rötung an der Anwendungsstelle) oder Lethargie auf. Diese hautirritierende Wirkung des Perme- thrins ist in der Literatur bekannt.DE 101 17676 A1 describes a two-ingredient mixture with 35 to 60% by weight of the active ingredient permethrin and 2.5 to 12% by weight of the active ingredient imidacloprid or imidacloprid analog. N-methylpyrrolidone is used as the carrier of the active ingredients. Other common pharmaceutically acceptable excipients such as e.g. Spreading agents and surfactants can be added. The publication claims that the product has excellent skin tolerance. However, the product of identical composition sold by the applicant of this patent application lists temporary skin hypersensitivity (including increased itching, hair loss and redness at the application site) or lethargy as possible side effects in dogs. This skin-irritating effect of permethrin is known in the literature.
Die DE 3531 920 A1 beschreibt ein Verfahren zur Herstellung eines Mittels zur Bekämpfung von Ektoparasiten bei Ziegen im Aufgießverfahren. Das Mittel enthält 0,01 bis 50 Gewichtsteile der Pyrethroide Cyfluthrin, Fenfluthrin, Flumethrin, Cyperme- thrin, Deltamethrin, deren Stereoisomere, Enantiomere oder Gemische sowie ein
hautverträgliches Verdünnungsmittel und ggf. Emulgatoren und Hilfsstoffe. Als geeignete Hilfsstoffe Haftvermittler, Tenside und Spreitmittel genannt.DE 3531 920 A1 describes a process for the production of an agent for controlling ectoparasites in goats in the pouring process. The agent contains 0.01 to 50 parts by weight of the pyrethroids cyfluthrin, fenfluthrin, flumethrin, cypermethrin, deltamethrin, their stereoisomers, enantiomers or mixtures and a Skin-compatible diluent and, if necessary, emulsifiers and auxiliaries. Adhesion promoters, surfactants and spreading agents mentioned as suitable auxiliaries.
Die DE 35 29 693 A1 beschreibt ein Mittel für ein Verfahren zur Behandlung von Herdentieren und vergesellschaftet lebenden Tieren zur Bekämpfung von Ektoparasiten. Das Mittel enthält Cyfluthrin, Flumethrin, Cypermethrin, Deltamethrin, Fenflu- thrin, deren Enantiomere oder Diastereomere oder Gemische derselben neben hautverträglichen Verdünnungsmitteln sowie ggf. Emulgatoren und weiteren Hilfsstoffen. Die Konzentration des Wirkstoffs beträgt 0,01 bis 10 Gew.-%.DE 35 29 693 A1 describes an agent for a method for treating herd animals and socialized animals for combating ectoparasites. The agent contains cyfluthrin, flumethrin, cypermethrin, deltamethrin, fenfluthrin, their enantiomers or diastereomers or mixtures thereof in addition to skin-compatible diluents and, if appropriate, emulsifiers and other auxiliaries. The concentration of the active ingredient is 0.01 to 10% by weight.
Die GB-A-2088212 offenbart eine flüssige Zusammensetzung, die bis zu ungefähr 50 Gew.-% eines Pyrethroids enthält und ein Verfahren für ihre topische Anwendung beinhaltet. Genauer gesagt offenbart die GB-A-2088212 die Lösung fester Pyrethroide in flüssiger Formulierung unter Verwendung unerwünschter irritierender organischer Lösungsmittel wie Xylol, Toluol und Cyclohexanon wahlweise in Verbindung mit Alkylglycolethem.GB-A-2088212 discloses a liquid composition containing up to about 50% by weight of a pyrethroid and including a method for its topical application. Specifically, GB-A-2088212 discloses the solution of solid pyrethroids in liquid formulation using undesirable irritating organic solvents such as xylene, toluene and cyclohexanone optionally in conjunction with alkyl glycol ether.
Die EP 0518 989 B1 und die DE 691 26776 T2 offenbaren flüssige Zusammensetzungen von mehr als 50 Gew.-% und bis zu 85 Gew.-% eines Pyrethroids sowie eines Trägers, der ein Alkylglycolether ist, um eine Zusammensetzung zur Kontrolle von Ektoparasiten auf domestizierte Säugetieren, gewählt aus Ratten, Mäusen, Kaninchen, Hunden, Rindvieh, Geflügel, Schweinen und Pferden, mittels topischer Anwendung herzustellen.EP 0518 989 B1 and DE 691 26776 T2 disclose liquid compositions of more than 50% by weight and up to 85% by weight of a pyrethroid and a carrier which is an alkyl glycol ether, for a composition for controlling ectoparasites on domesticated To produce mammals selected from rats, mice, rabbits, dogs, cattle, poultry, pigs and horses by topical application.
Die genannte Erfindung umfaßt 65 Gew.-% bis 85 Gew.-% Permethrin und einen Akylglycolether als Träger. Dabei wird als neu und überraschend herausgestellt, daß diese konzentrierende Formulierung keine Irritation oder Toxizität auf der Haut hervorruft. Es wäre zu erwarten, daß derart hochkonzentrierte Lösungen eines Pyrethroids, wenn auf die Haut appliziert und von dort resorbiert, außerdem systemische
Toxizität bewirken würden.The invention mentioned comprises 65% to 85% by weight of permethrin and an alkyl glycol ether as carrier. It is pointed out as new and surprising that this concentrating formulation does not cause any irritation or toxicity on the skin. It would be expected that such highly concentrated solutions of a pyrethroid, when applied to and absorbed from the skin, would also be systemic Would cause toxicity.
Dieser Anspruch des Patentes EP 0518 989 B1 und DE 691 26 776 T2 ist nicht aufrechtzuerhalten. Die jahrzehntelange erfolgreiche Vermarktung des einzigen Produktes mit der genannten Applikationsform ist als „Exspot®" der Firma ESSEX TIERARZNEI, Thomas-Dehler Str. 27, 8737 München, im Handel. Dieses Produkt, wie auch ein weiteres mit Wirkung vom 26.04.2003 zugelassenes, derzeit nicht im Handel befindliches Arzneimittel „FLETIC®" der Firma Supplexan, 22085 Hamburg, Schenkendorfstr. 15, haben auf Anordnung der Arzneimittel-Zulassungsbehörde als Nebenwirkungen aufzuführen: „An der Applikationsstelle kann Juckreiz auftreten, gelegentlich kann es zu Haarausfall und Blasenbildung an der Applikationsstelle kommen". Diese unerwünschten Effekte, die von Tieren, Tierärzten und Tierbesitzern als sehr unangenehm empfunden werden, sind literaturbekannte Eigenschaften des Permethrins und in ihrer Intensität direkt abhängig von der Konzentration und Verweildauer des Wirkstoffes auf der Haut. Humanmedizinische Kasuistiken und epidemiologische Studien beschreiben als Nebenwirkung von Pyrethroiden Pa- rästhesien auf der Haut (Kribbeln, Brennen usw.). Diese Effekte können mit einer Latenzzeit von wenigen Minuten bis zu mehreren Stunden nach Hautkontakt von unverdünntem Permethrin oder anwendungsbereiten Lösungen kommen.This claim of the patent EP 0518 989 B1 and DE 691 26 776 T2 cannot be maintained. The decades of successful marketing of the only product with the application form mentioned is commercially available as "Exspot ® " from ESSEX TIERARZNEI, Thomas-Dehler Str. 27, 8737 Munich. This product, as well as another one approved with effect from April 26, 2003, Medicinal product "FLETIC ® " from Supplexan, 22085 Hamburg, Schenkendorfstr. 15, on the orders of the drug licensing authority, list the following as side effects: "Itching may occur at the application site, occasionally hair loss and blistering may occur at the application site". These undesirable effects, which animals, veterinarians and pet owners find very unpleasant , Permethrin properties known from the literature and their intensity directly depend on the concentration and length of time of the active substance on the skin. Human medical reports and epidemiological studies describe paresthesias on the skin as a side effect of pyrethroid (tingling, burning, etc.). These effects can with a latency period of a few minutes to several hours after skin contact of undiluted permethrin or ready-to-use solutions.
Die in den Patenten EP 0518989 B1 und DE 691 26776 T2 verwendeten Hilfsmittel (Lösungsmittel) gehören der Stoffklasse der Alkylglycolether an. Es handelt sich dabei um fast geruchlose Flüssigkeiten mit hohem Siedepunkt, sehr guter Löslichkeit in Wasser und sehr guter Mischbarkeit mit organischen Lösungsmitteln. Bei Alkylglycolether handelt es sich meistens um hygroskopische Flüssigkeiten, die zumindest bei dermaler Applikation als untoxisch gelten (LD 50 dermal Kaninchen 6450 mg/kg KG). Ihr Einsatz in der Dermatologie als penetrationsfördernde Hilfsmittel ist umstritten, da auch eine Penetrationsreduzierung, abhängig von der Formulierung, durch sie auftreten kann. Insbesondere können die hygroskopischen Eigenschaften
dieser Lösungsmittelgruppe zusätzlich nachteilig im Hinblick auf das Penetrieren von hydrophoben Wirkstoffen durch die Haut sein.The auxiliaries (solvents) used in patents EP 0518989 B1 and DE 691 26776 T2 belong to the class of alkyl glycol ethers. These are almost odorless liquids with a high boiling point, very good solubility in water and very good miscibility with organic solvents. Alkyl glycol ethers are mostly hygroscopic liquids that are considered non-toxic, at least when dermally applied (LD 50 dermal rabbit 6450 mg / kg body weight). Their use in dermatology as a penetration-enhancing aid is controversial, since it can also reduce penetration, depending on the formulation. In particular, the hygroscopic properties this group of solvents may also be disadvantageous with regard to the penetration of hydrophobic active substances through the skin.
Bedingt durch die gute Wasserlöslichkeit des Alkylglykolethers wird die Zuammen- setzung nach dem Auftragen auf die Haut des zu behandelnden Tieres bei Kontakt mit Wasser, z.B. durch Regen oder beim Baden, von dem Tier abgewaschen. Hierdurch entsteht ein wirtschaftlicher Schaden, da die Lösung anschließend neu aufgetragen werden muß. Zudem kann das in die Umwelt gelangte Permethrin die Umwelt unnötig belasten. Ein weiterer Nachteil dieser Zusammensetzung besteht darin, daß die Lösung bedingt durch die hygroskopischen Eigenschaften des Alkylglykolethers, schnell Wasser aufnimmt, wodurch unerwünschte Trübungen in der Zusammensetzung entstehen. Um diese Trübungen zu verhindern, müssen aufwendige und teure Bedingungen während der Herstellung der Zusammensetzung eingehalten werden.Due to the good water solubility of the alkyl glycol ether, the composition after application to the skin of the animal to be treated is in contact with water, e.g. washed off the animal by rain or bathing. This causes economic damage because the solution must then be reapplied. In addition, the permethrin released into the environment can unnecessarily pollute the environment. Another disadvantage of this composition is that, due to the hygroscopic properties of the alkyl glycol ether, the solution quickly absorbs water, which causes undesirable cloudiness in the composition. In order to prevent this cloudiness, complex and expensive conditions must be observed during the preparation of the composition.
Die Erfindung befaßt sich mit dem Problem, eine parasitizide und repellierende Zusammensetzung mit dem Wirkstoff Permethrin zur topischen Anwendung auf domestizierten Tieren bereitzustellen, die bei hoher Wirksamkeit und einfach anzuwenden ist, keine Hautirritationen im Anwendungsbereich verursacht und kostengünstig sowie umweltschonend in der Herstellung bzw. Anwendung ist.The invention is concerned with the problem of providing a parasiticidal and repellant composition with the active ingredient permethrin for topical use on domesticated animals which is highly effective and easy to use, does not cause skin irritation in the area of application and is inexpensive and environmentally friendly to produce or use ,
Die Erfindung löst dieses Problem durch eine Zusammensetzung mit den Merkmalen des Patentanspruchs 1.The invention solves this problem by a composition having the features of claim 1.
Bei der erfindungsgemäßen Zusammensetzung wird Permethrin in einer sehr hohen Konzentration von 50 bis 90 Gew.-% in Isopropylmyristat gelöst. Überraschenderweise wurde festgestellt, daß speziell dieser Trägerstoff nicht nur als Lösungsmittel fungiert, sondern gleichzeitig eine Carrier-Funktion (Transportfunktion) übernimmt und das Permethrin schnell von der Hautoberfläche weg in die fetthaltigen, tiefgelegenen Fellschichten der Hornhaut (stratum cornum) transportiert, die der Oberhaut
(Epidermis) zuzurechen sind, und es dort keine Hautirritationen mehr auslöst aber dennoch wirksam ist. Gleichzeitig wird durch diesen schnellen Transport des Perme- thrins von der Hautoberfläche weg ein Auswaschen durch Kontakt mit Wasser verhindert.In the composition according to the invention, permethrin is dissolved in isopropyl myristate in a very high concentration of 50 to 90% by weight. Surprisingly, it was found that this carrier in particular not only acts as a solvent, but at the same time assumes a carrier function (transport function) and quickly transports the permethrin away from the surface of the skin into the deep fat layers of the cornea (stratum cornum), those of the epidermis (Epidermis) and it no longer causes skin irritation but is still effective. At the same time, this rapid transport of permethrin away from the skin surface prevents washing out by contact with water.
Es ist überraschend zu erkennen, daß die insektizide Zusammensetzung der vorliegenden Erfindung mit einem derart hohen Prozentsatz des aktiven Inhaltstoffes Permethrin als Wirkstoff und Isopropylmyristat als Trägerstoff gegen Ektoparasiten wirksam ist und dabei im Gegensatz zu den vorgenannten Erfindungen und den aus ihnen resultierenden Arzneimittel-Zulassungen keinerlei Hautirritationen und Hautschäden herbeiführt. Die erfindungsgemäße Zusammensetzung, mit einem Perme- tringehalt, der ohne Isopropylmyristat zu Hautunverträglichkeiten führen würde, gestattet die Verabreichung kleiner, leicht applizierbarer Dosen in Verbindung mit dem genannten Lösungsmittel ohne Nebenwirkungen. Hierfür ist keine besondere Sachkenntnis, wie bei der Verabreichung mit Hilfe einer Spritze erforderlich. Auch wird die häufig für den Tierbesitzer gefährliche Zwangverabreichung von Tabletten vermieden.It is surprising to see that the insecticidal composition of the present invention with such a high percentage of the active ingredient permethrin as active ingredient and isopropyl myristate as carrier is effective against ectoparasites and, in contrast to the aforementioned inventions and the drug approvals resulting therefrom, does not cause any skin irritation and causes skin damage. The composition according to the invention, with a permetrin content which would lead to skin intolerance without isopropyl myristate, permits the administration of small, easily applicable doses in conjunction with the solvent mentioned without side effects. No special expertise is required for this, as is the case with administration using a syringe. The forced administration of tablets, which is often dangerous for the pet owner, is also avoided.
Permethrin hat ein Molgewicht von 391,29 g/mol und technisches Permethrin umfaßt ungefähr 25 bis 80 Gew.-% eis- und ungefähr 20 bis 75 Gew.-% trans-lsomer. Für die vorliegende Erfindung ist technisch hergestelltes Permethrin besonders geeignet. Insbesondere geeignet ist eine Minimalmenge des trans-lsomers von ungefähr 45 Gew.-% und eine Minimalmenge des cis-lsomers von 35 Gew.-%.Permethrin has a molecular weight of 391.29 g / mol and technical permethrin comprises approximately 25 to 80% by weight of ice and approximately 20 to 75% by weight of trans-isomer. Technically produced permethrin is particularly suitable for the present invention. A minimum amount of the trans-isomer of approximately 45% by weight and a minimum amount of the cis-isomer of 35% by weight are particularly suitable.
Bei einer bevorzugten Ausgestaltung der Erfindung enthält die Zusammensetzung 65 Gew.-% Permethrin und 35 Gew.-% Isopropylmyristat als Trägerstoff, wobei das Permitrin vorzugsweise eine Minimalmenge des trans-lsomers von 45 Gew.-% und eine Minimalmenge des cis-lsomers von 35 Gew.-% aufweist.
Fettsäureester, insbesondere Isopropylmyristat, zeichnen sich durch hohe oxidative und hydrolytische Stabilität aus. Eine besondere Eigenschaft dieser Substanz liegt in der ausgezeichneten Spreitbarkeit (Verteilung auf der Haut) und dem besonders schnellen Einziehen in die oberen Hautschichten. Bei einer hervorragenden Mischbarkeit mit Ölen und lipophilen Substanzen ist die Substanz nicht mit Wasser mischbar.In a preferred embodiment of the invention, the composition contains 65% by weight of permethrin and 35% by weight of isopropyl myristate as a carrier, the permitrin preferably having a minimum amount of the trans-isomer of 45% by weight and a minimum amount of the cis-isomer of 35 % By weight. Fatty acid esters, especially isopropyl myristate, are characterized by high oxidative and hydrolytic stability. A special property of this substance is the excellent spreadability (distribution on the skin) and the particularly quick absorption into the upper layers of the skin. With excellent miscibility with oils and lipophilic substances, the substance is not miscible with water.
Es war überraschend zu erkennen, daß schon eine verhältnismäßig kurze Reduktion der Verweildauer auf der Haut durch Verwendung des neuen Lösungsmittels Isopropylmyristat zu einer nahezu 100 %-igen Reduktion der Hautirritationen von Permethrin bei dermaler Applikation als sog. Spot-on-Formulierung führte (s. Kasuistik der beigefügten Hautverträglichkeitsstudie bei Hunden).It was surprising to see that a relatively short reduction in the length of stay on the skin by using the new solvent isopropyl myristate led to an almost 100% reduction in skin irritation from permethrin during dermal application as a so-called spot-on formulation (see Case report of the attached skin tolerance study in dogs).
Neu und überraschend für Fachleute ist daher, daß durch die kurze Verweildauer des Permethrins bei Verwendung von Isopropylmyristat als Trägersubstanz Irritationen und Hautschäden, wie sie immer wieder bei der Verwendung anderer Trägersubstanzen als Lösungsmittel als äußerst unerwünschte Nebenwirkungen beobachtet werden, nicht auftreten. Diese neue Erkenntnis stellt aus Gründen des Tierschutzes und der Anwender-Compliance einen erheblichen Fortschritt dar.What is new and surprising for experts is therefore that the short residence time of permethrin when isopropyl myristate is used as the carrier substance means that irritations and skin damage, as are repeatedly observed as extremely undesirable side effects when using other carrier substances as solvents, do not occur. This new finding represents significant progress for reasons of animal welfare and user compliance.
Die Erklärung dafür ist darin begründet, daß die Trägersubstanz in Verbindung mit hydrophoben Substanzen zu einem schnellen Eindringen der Trägersubstanz in die Lipidbereiche der Unterhaut oder genauer, in den Bereich der fetthaltigen, tief gelegenen Fellschichten der Hornhaut (stratum cornum), die der Oberhaut (epidermis) zuzurechnen sind, führt. Bedingt durch die hydrophobe Eigenschaft des Isopropyl- myristats dringt das Permethrin nicht in dort befindliche Blutgefäße ein, was zur Folge hätte, daß das Permethrin systemisch wirken würde und z.B. unerwünschte Lethargien auslösen könnte.
Die vorliegende Erfindung beruht auf der Erkenntnis, daß eine schnellere Penetration des Permethrins durch die äußere Hautschicht die Aufnahmegeschwindigkeit des Arzneimittels erhöht und damit die Verweildauer auf der Haut reduziert.The explanation for this is based on the fact that the carrier substance in conjunction with hydrophobic substances allows the carrier substance to penetrate rapidly into the lipid areas of the subcutis or, more precisely, into the area of the fatty, deep-lying layers of fur of the cornea (stratum cornum), that of the epidermis ) are attributable to leads. Due to the hydrophobic property of the isopropyl myristate, the permethrin does not penetrate the blood vessels located there, which would have the consequence that the permethrin would have a systemic effect and could, for example, trigger undesired lethargy. The present invention is based on the finding that a faster penetration of the permethrin through the outer skin layer increases the rate of absorption of the drug and thus reduces the length of stay on the skin.
Literaturbekannt ist außerdem, daß die Wirkung von Permethrin dosisabhängig ist. Demzufolge wäre mit einer Verbesserung der Resorptionsrate und -geschwindigkeit grundsätzlich eine Dosiserhöhung zu erreichen. Dieser Nebeneffekt der vorliegenden Erfindung hat insofern Bedeutung, als auf der einen Seite literaturbekannt systemisch toxische Effekte des Permethrins bei Säugetieren in weiten Bereichen nicht annährend erreicht werden, auf der anderen Seite aber die toxischen Effekte auf der Haut eine Dosiserhöhung des Wirkstoffes bei der vorliegenden Applikationsform verbieten.It is also known from the literature that the effect of permethrin is dose-dependent. Accordingly, an increase in the absorption rate and rate would fundamentally lead to a dose increase. This side effect of the present invention is important insofar as, on the one hand, systemic toxic effects of permethrin in mammals are not nearly achieved in a manner known from the literature, but on the other hand, the toxic effects on the skin prohibit an increase in the dose of the active ingredient in the present application form ,
Nach der vorliegenden Erfindung wird indirekt eine Dosiserhöhung dadurch erreicht, daß mit Hilfe des verwendeten Lösungsmittels eine schnellere und stärkere Resorption des Wirkstoffs in das Unterhautfettgewebe bzw. genauer in den Bereich der fetthaltigen, tief gelegenen Fellschichten der Hornhaut (stratum cornum) erfolgt.According to the present invention, an increase in dose is achieved indirectly by using the solvent used for a faster and stronger absorption of the active substance into the subcutaneous fatty tissue or more precisely into the area of the fat-containing, deep-lying layers of the cornea (stratum cornum).
Neu und bedeutungsvoll ist außerdem, daß durch die rein lipophile Formulierung wie z.B. bei der Verwendung des Fettsäureesthers Isopropylmyristat ein Auswaschen des Wirkstoffs durch Baden unterbleibt und somit die Wirkungsdauer von vier Wochen nicht unterbrochen wird. Neu und eine Folge davon ist darüber hinaus, daß dadurch, daß die Erfindung aus wasserunlöslichen Bestandteilen besteht, ein erheblicher Beitrag zum Umweltschutz geleistet wird in der Weise, daß bei versehentlichem Baden, insbesondere von Hunden, kein Wirkstoff in die Natur gelangt.What is also new and significant is that the purely lipophilic formulation, e.g. When using the fatty acid ester isopropyl myristate, the active ingredient is not washed out by bathing and the duration of action of four weeks is not interrupted. New and a consequence of this is that the fact that the invention consists of water-insoluble constituents makes a significant contribution to environmental protection in such a way that no accidental bathing, especially of dogs, gets into the nature.
Isopropylmyristat ist zudem nicht hygroskopisch, so daß keine galenischen Probleme in Form von Trübungen bei der Herstellung auftreten. Entsprechend sind auch keine teuren Maßnahmen zur Verhinderung dieser Trübungen notwendig.
Weitere Lösungsmittel könnten organische Substanzen wie einfache und mehrwertige Alkohole, Ester, Ketone, organische Salze und Säuren sein, wenn sie in ihren physikalischen und toxischen Eigenschaften dem verwendeten Trägerstoff Isopropylmyristat entsprechen und mit Permethrin kompatibel sind. Insbesondere eignen sich zudem 1-Butanol und Triglyceride mit mittelkettigen Fettsäuren, insbesondere ein Gemisch von Triglyceridestem gesättigter, mittelkettiger Fettsäuren, meist natürlicher Herkunft, mit einem geringen Anteil ungesättigter Fettsäuren. Diese Substanzen haben eine gute Stabilität und ein hervorragendes Hauteindringungsvermögen.Isopropyl myristate is also not hygroscopic, so that there are no galenical problems in the form of turbidity during production. Accordingly, no expensive measures to prevent this clouding are necessary. Other solvents could be organic substances such as simple and polyhydric alcohols, esters, ketones, organic salts and acids if their physical and toxic properties correspond to the carrier isopropyl myristate used and are compatible with permethrin. In addition, 1-butanol and triglycerides with medium-chain fatty acids are particularly suitable, in particular a mixture of triglyceride esters of saturated, medium-chain fatty acids, mostly of natural origin, with a small proportion of unsaturated fatty acids. These substances have good stability and excellent skin penetration properties.
Als weitere Inhaltsstoffe können der vorliegenden Zusammensetzung Verteilungsagenzien, Lockmittel, Repellentien, Haftvermittler, Spreitmittel, Stabilisatoren, Kondi- tionierer, Parfüms, Fellglänzmittel und Farbagenzien hinzugefügt werden. Derartige Substanzen sind literaturbekannt und finden in der kosmetischen Industrie breite Anwendung.Distribution agents, attractants, repellents, adhesion promoters, spreading agents, stabilizers, conditioners, perfumes, fur gloss agents and color agents can be added to the present composition as further ingredients. Such substances are known from the literature and are widely used in the cosmetic industry.
Um die insektizide Zusammensetzung der vorliegenden Erfindung herzustellen, wird das Pyrethroid zur vollständigen Lösung eventuell vorhandener Kristalle auf 65 °C bis 80 °C erwärmt. Das flüssige Lösungsmittel wird in ein getrenntes, nicht erwärmtes Reaktionsgefäß gegeben, dem das Permethrin zugefügt und bis zur Gleichmäßigkeit vermischt wird. Pharmazeutische und kosmetische Additive können zuvor dem Reaktionsgefäß zugesetzt werden. Die Zusammensetzung kann auf das Wirtstier mittels jeglicher herkömmlicher Methoden für die lokale Applikation verabreicht werden. Dabei ist literaturbekannt, daß bei der geschilderten Konzentration und Menge des Wirkstoffs ein 1-ml-Volumen der bevorzugten Flüssigkeitszusammensetzung bei Hunden mit weniger als 15 kg Körpergewischt ausreichend wirksam ist. Ein 1-2-ml-Volumen des bevorzugten 65 Gew.-% Permethrin (65 mg bis 130 mg Permethrin) ist ausreichend für Hunde, die größer als 15 kg sind. Dafür werden 1 ml der genannten Lösung zwischen die Schulterblätter und 1 weiterer ml an der
Schanzwurzel, d.h. am oberen Ende, nachdem die Haare geteilt wurden, appliziert. Nachfolgend werden erfindungsgemäße Zusammensetzungen beispielhaft aufgeführt und erläutert:To prepare the insecticidal composition of the present invention, the pyrethroid is heated to 65 ° C to 80 ° C to completely dissolve any crystals present. The liquid solvent is placed in a separate, non-heated reaction vessel to which the permethrin is added and mixed until uniform. Pharmaceutical and cosmetic additives can be added to the reaction vessel beforehand. The composition can be administered to the host animal by any conventional local application method. It is known from the literature that a 1 ml volume of the preferred liquid composition is sufficiently effective in dogs with less than 15 kg of body weight given the concentration and amount of active ingredient described. A 1-2 ml volume of the preferred 65% by weight permethrin (65 mg to 130 mg permethrin) is sufficient for dogs larger than 15 kg. For this, 1 ml of the solution mentioned is placed between the shoulder blades and 1 further ml of the Bulwark, ie applied at the upper end after the hair was split. Compositions according to the invention are listed and explained below by way of example:
Produkt 1 : 65 Gew.-% Permethrin + 35 Gew.-% n-1 -ButanolProduct 1: 65% by weight permethrin + 35% by weight n-1-butanol
Produkt 2: 65 Gew.-% Permethrin + 35 Gew.-% IsopropylmyristatProduct 2: 65% by weight permethrin + 35% by weight isopropyl myristate
Produkt 3: 65 Gew.-% Permethrin + 35 Gew.-% TriglycerideProduct 3: 65% by weight permethrin + 35% by weight triglycerides
Die drei Produkte wurden in In-vivo-Untersuchungen hinsichtlich möglicher Hautirritationen untersucht. Die Untersuchungsprotokolle sind nachfolgend beigefügt. Es zeigt sich, daß keine Hautirritationen in Form von Brennen, Juckreiz und Hautschäden festgestellt werden konnten. Den Untersuchern waren die Lösungsmittel der mit 1 , 2, 3 bezeichneten Produkte nicht bekannt.The three products were examined in vivo for possible skin irritation. The test reports are attached below. It turns out that no skin irritation in the form of burning, itching and skin damage could be found. The investigators were not aware of the solvents of the products labeled 1, 2, 3.
Die obige Hautverträglichkeitsstudie wurde von fünf unabhängigen praktizierenden Tierärzten und einem pharmazeutischen Sachverständigen durchgeführt. Sie umfaßte Hunde aus verschiedenen Rassen, weibliche sowie Rüden, im Alter von 10 Wochen bis 8 Jahren. In zwei Fällen wurde eine schwache Hautreaktion beobachtet (Produkt 1). Alle übrigen Tiere zeigten auch in den Tagen nach der Applikation keine Nebenwirkungen, wie sie z.B. bei der Verwendung von 2-(2-Methylethoxy)ethanol laut Produktinformation EXSPOT® beschrieben werden.The above skin tolerance study was carried out by five independent practicing veterinarians and a pharmaceutical expert. It included dogs of different breeds, female and male, from the age of 10 weeks to 8 years. A weak skin reaction was observed in two cases (product 1). All other animals showed no side effects in the days after the application, as described for example when using 2- (2-methylethoxy) ethanol according to the product information EXSPOT ® .
Die verwendeten, in einfacher Blindstudie geprüften Produkte sind problemlos anwendbar und stellen aufgrund ihrer reaktionslosen Anwendung einen Fortschritt gegenüber der bisherigen Formulierung dar. Darüber hinaus sind die geprüften Trägerstoffe aufgrund ihres chemisch-physikalischen Verhaltens jeweils für verschiedene Verpackungsformen (Glas, Kunststoff) geeignet.
The products used, which have been tested in a simple blind study, can be used without any problems and, because of their unresponsive application, represent an advance over the previous formulation. In addition, the tested carriers are suitable for different packaging forms (glass, plastic) due to their chemical-physical behavior.
Claims
1. Parasitizide und repellierende Zusammensetzung zur topischen Anwendung auf domestizierten Tieren, enthaltend 50 - 90 Gew.-% Permethrin oder dessen Stereoisomere und Isopropylmyristat in einer zum erreichen von 100 Gew.-% erforderlichen Menge.1. Parasiticides and repellant composition for topical use on domesticated animals, containing 50-90% by weight of permethrin or its stereoisomers and isopropyl myristate in an amount necessary to achieve 100% by weight.
2. Zusammensetzung nach Anspruch 1 , dadurch gekennzeichnet, daß das Permethrin 25 bis 80 Gew.-% eis- und ungefähr 20 bis 75 Gew.-% trans-lsomer enhält.2. Composition according to claim 1, characterized in that the permethrin contains 25 to 80 wt .-% ice and about 20 to 75 wt .-% trans isomer.
3. Zusammensetzung nach einem der vorherigen Ansprüche, dadurch gekennzeichnet, daß sie 60 bis 90 Gew.-% Permethrin enthält.3. Composition according to one of the preceding claims, characterized in that it contains 60 to 90 wt .-% permethrin.
4. Zusammensetzung nach einem der vorherigen Ansprüche, dadurch gekennzeichnet, daß sie 65 Gew.-% Permethrin enthält. 4. Composition according to one of the preceding claims, characterized in that it contains 65 wt .-% permethrin.
5. Zusammensetzung nach einem der vorherigen Ansprüche, dadurch gekennzeichnet, daß die domestizierten Tiere, Hunde und/oder Pferde sind.5. Composition according to one of the preceding claims, characterized in that the domesticated animals are dogs and / or horses.
6. Zusammensetzung nach einem der vorherigen Ansprüche, dadurch gekennzeichnet, daß sie weitere pharmazeutische und kosmetische Additive enthält. 6. Composition according to one of the preceding claims, characterized in that it contains further pharmaceutical and cosmetic additives.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10329993 | 2003-07-02 | ||
| DE10337305A DE10337305A1 (en) | 2003-07-02 | 2003-08-14 | Parasiticides, repellant composition and process for their preparation and use |
| PCT/EP2004/007163 WO2005002339A1 (en) | 2003-07-02 | 2004-07-01 | Parasiticidal, repellent composition for topical use on domestic animals |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP1638404A1 true EP1638404A1 (en) | 2006-03-29 |
| EP1638404B1 EP1638404B1 (en) | 2007-08-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP04740530A Not-in-force EP1638404B1 (en) | 2003-07-02 | 2004-07-01 | Parasiticidal, repellent composition for topical use on domestic animals |
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| Country | Link |
|---|---|
| EP (1) | EP1638404B1 (en) |
| AT (1) | ATE370658T1 (en) |
| DE (1) | DE502004004739D1 (en) |
| WO (1) | WO2005002339A1 (en) |
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| CH702717A2 (en) | 2010-02-26 | 2011-08-31 | Solnova Ag | Spot-on preparation. |
| DE202012004045U1 (en) | 2012-04-16 | 2012-05-02 | Solnova Ag | Spot-on preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0125471A3 (en) * | 1983-04-07 | 1986-09-17 | The Wellcome Foundation Limited | Pesticidal composition |
| ATE155007T1 (en) * | 1990-03-05 | 1997-07-15 | Mallinckrodt Veterinary Inc | PARASITICIDAL COMPOSITION AND METHOD FOR PREPARATION THEREOF AND USE THEREOF |
-
2004
- 2004-07-01 DE DE502004004739T patent/DE502004004739D1/en active Active
- 2004-07-01 EP EP04740530A patent/EP1638404B1/en not_active Not-in-force
- 2004-07-01 WO PCT/EP2004/007163 patent/WO2005002339A1/en active IP Right Grant
- 2004-07-01 AT AT04740530T patent/ATE370658T1/en active
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| DE502004004739D1 (en) | 2007-10-04 |
| WO2005002339A1 (en) | 2005-01-13 |
| EP1638404B1 (en) | 2007-08-22 |
| ATE370658T1 (en) | 2007-09-15 |
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